Proton sponge → HCID 131732860, compound

HRID 576122Notes

Reaction equation

HRID 576122 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([C:20]4[N:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11](C)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.ClC(OC(Cl)C)=O.[C:54]([OH:63])(=[O:62])[C@@H:55]([C@H:57]([C:59]([OH:61])=[O:60])[OH:58])[OH:56]>ClCCCl.C(Cl)Cl.C(#N)C.O>[C:59]([C@@H:57]([C@H:55]([C:54]([OH:63])=[O:62])[OH:56])[OH:58])([OH:61])=[O:60].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([C:20]4[N:21]=[N:22][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:24][CH:25]=4)=[C:16]([F:19])[CH:17]=3)[CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]

Participants

9

Reactant 4

HCID 88675Proton spongeHCID 444305L-Tartaric acidHCID 5213051-Chloroethyl chloroformateHCID 86647720HCID 86647720, compound

Product 1

HCID 131732860HCID 131732860, compoundYield 132.2%

Reagents, catalysts & solvents 4

HCID 111,2-DichloroethaneSolventHCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Procedure

To (+)-4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline (320 mg, 0.70 mmol) and N1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine (299 mg, 0.70 mmol) in 1,2-dichloroethane (5 mL) was added 1-chlorethyl chloroformate (0.15 mL, 1.4 mmol) drop wise. The mixture was heated to reflux for 3 hours and then cooled to ambient temperature. The reaction mixture was diluted with methylene chloride (30 mL) and washed with 1N HCl (10 mL), water (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. To the residue was added methanol (15 mL) and the mixture was heated to reflux. After 1 hour, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was taken up in ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (10 mL), water (10 mL), brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (methylene chloride to 90:9:1 methylene chloride/methanol/ammonium hydroxide) and preparative TLC (90:9:1 methylene chloride/methanol/ammonium hydroxide). To the obtained material in acetonitrile (1.5 mL) was added L-tartaric acid (9.2 mg, 0.06 mmol) in water (5 mL). The resultant solution was lyophilized to give (+)-4-(3,4-dichlorophenyl)-6-fluoro-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline, L-tartrate salt (47 mg, 11%) as a white powder: 1H NMR (CD3OD, 500 MHz) δ 8.32 (d, J=8.5 Hz, 1H), 8.19 (d, J=9.0 Hz, 1H), 8.07 (d, J=7.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.51 (d, J=1.5 Hz, 1H), 7.24 (dd, J=8.5, 2.0 Hz, 1H), 6.85 (d, J=11.5 Hz, 1H), 4.59-4.48 (m, 3H), 4.41 (s, 1.8H), 3.77-3.71 (m, 1H), 3.40-3.38 (m, 1H); ESI MS m/z 442 [M+H]+.

Workup

  1. temperatureThe mixture was heated
  2. temperatureto reflux for 3 hours
  3. washwashed with 1N HCl (10 mL), water (10 mL)
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. additionTo the residue was added methanol (15 mL)
  8. temperaturethe mixture was heated to reflux
  9. temperaturethe reaction mixture was cooled to ambient temperature
  10. concentrationconcentrated under reduced pressure
  11. washwashed with saturated aqueous sodium bicarbonate (10 mL), water (10 mL), brine (10 mL)
  12. dry with materialdried over sodium sulfate
  13. filtrationfiltered
  14. concentrationconcentrated in vacuo
  15. customThe residue was purified by column chromatography (methylene chloride to 90:9:1 methylene chloride/methanol/ammonium hydroxide) and preparative TLC (90:9:1 methylene chloride/methanol/ammonium hydroxide)

Sources & evidence

ORD record
ord-bc7ee5312ce6465ba215f191c2c0d2d9
Source dataset
uspto-grants-2015_05
Patent number
US09034899B2

Reaction notes

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